This Research scientist Development Award has a short term goal to improve clinical trials methodology for pharmacotherapy of cocaine abuse and a long term goal to develop several neurobiologic methods to select more homogeneous groups of cocaine abusing opioid addicts for these pharmacotherapies. The first Specific Aim is to examine the combination of desipramine (DMI) with buprenorphine (BUP) in a randomized, placebo controlled clinical trial of 160 patients. A second Specific Aim under Dr. Rounsaville's mentoring is to examine two prognostic factors: depression and gender. These two Specific Aims are related to the Aim of my Career award to develop clinical trials methodology for the pharmacotherapy of diagnostically and prognostically homogeneous substance abusers, and they build on my clinical trials over the last five years with BUP and DMI. For my long term goal, I will work with Dr. Heninger and the Ribicoff Research faculty to become educated about and to develop, evaluate and apply neurobiologic tests (e.g. pharmacologic challenges, receptor and second messenger assessments, diagnostic imaging of brain neuroreceptors, new methods from molecular neurobiology) in order to identify more homogeneous patient groups. My career plans in clinical trials methodology under Dr. Feinstein include developing craving assessments, testing clinical strategies for analyzing quantitative urine toxicologies, and adapting cross-over and discontinuation research designs for drug dependence. The Yale Treatment Research Unit and Substance Abuse Research Center also have provided me with outstanding collaborators for clinical trials of mazindol, bupropion, and theophylline. Because of this strong and expanding group of mentors and collaborators, the proposed research program will be capable of maintaining the high productivity of its last five years.